The rusty genotypes

Two main genetic entities lead to iron overload: hemochromatosis and thalas semia. Genetic hemochromatosis HFE-1 type is a common autosomal recessive d isease affecting about 1/300 individuals of european descent. HFE-1 type he mochromatosis is associated with the C282Y mutation of the HFE gene, and th e H63D mutation to a much lesser degree. Allele frequency of the C282Y type is about 6,6 % in Europe and the average of the H63D allele frequency is a bout 13,4 %. Thalassemia is prevalent in a wide belt of countries extending from the mediterranean basin down to Africa and through the Middle East, t he indian subcontinent and into south east Asia and China. Population genet ic studies show that thalassemias are common where primary hemochromatosis is not. There is little reproductive disavantage to C282Y homozygotes and e ven less to heterozygotes. No major disvantage appears for the H63D mutatio n. Our results suggest that there is or has been selection pressure favorin g these mutations making genetic drift an unlikely explanation. Until now i t has been assumed that the selective advantage conferred by HFE mutations was the prevention of iron deficiency; this would include protection agains t anemia due to hookworm infestation, multiples pregnancies, a diet lacking in iron or any combination of these factors. However if this were solely t he case, then one might expect that one more of the HFE mutations would hav e reached fixation in countries where there are high levels of anemia; this has not been observed yet. Because of wild-type HFE protein is expressed a t the cell surface, one could speculate that this protein is the receptor f or some infectious agents. The region of the protein that might be involved could be the exon 3 which encodes the alpha 1 domain where the H63D mutati on is found. The C282Y mutation does not allow the HFE-1 protein to reach t he cell surface. Like thalassemia, hemochromatosis could be the result of a selection pressure involving resistance to infectious agent. By now, the e ntire world population carries an unfortunate genetic burden leading to iro n overload.